The Collaborative Research Center for American Indian Health (CRCAIH) is designed to create a communication and infrastructure platform to bring together Tribal communities and health researchers, from a variety of disciplines, to work together in the development of cutting-edge transdisciplinary research to address the significant health disparities experienced by American Indians in South Dakota, North Dakota and Minnesota. All projects within the CRCAIH will embrace a social determinants of health theme. This theme was selected because of the needs of the region, the immediate applicability of many social determinants of health to public health intervention programming and the existing strengths within the consortium of partners. The overarching specific aims of the CRCAIH are (1) create a collaborative infrastructure for the active discussion, planning and implementation of transdisciplinary research projects by Tribal communities and health researchers that are designed to address health disparities in American Indian populations in the region; (2) increase the capacity of Tribal communities in all aspects of the research process, including the provision of training and technical assistance to build skills that will provide a foundation for Tribes to develop, conduct and participate in ongoing and future research projects; (3) support three novel and innovative transdisciplinary research projects that address significant areas of health disparities in American Indian populations of the Northern Plains; and (4) create a mechanism to support and monitor a pilot grant program that funds research studies aligned with CRCAIH goals and have a high probability of leading to meaningful results and sustainability.